Infectious viral diseases are recognized as an important medical problem. Progress against infectious viral diseases requires the development of drugs with selective antiviral activity while remaining benign to normal cell lines. A number of antiviral agents currently under study which seem to possess some selectivity, are nucleoside analogs. In general, these compounds are structural analogs of the naturally occurring nucleosides. Structural modification in either the purine or pyrimidine base nucleus and/or the saccharide component results in a synthetically modified nucleoside derivative which, when incorporated into a viral nucleic acid forming process, acts to disrupt further synthesis of viral nucleic acid. Effectiveness of these antiviral agents depends on selective conversion by viral enzymes, but not by host enzymes, to the corresponding nucleotide analog which is then converted to the triphosphate and incorporation into vital nucleic acid occurs. A problem with this antiviral strategy has been the emergence of certain viral strains whose enzymes poorly promote phosphorylation of the nucleoside analogs. To circumvent this problem, intact nucleotide analogs appear to be potentially quite useful as antivirals for incorporation into viral nucleic acid.
Reist and Sturm in WO84/04748, published Dec. 6, 1984, disclosed new phosphonic acid analogs of nucleoside phosphates which are useful as antivirals for incorporation into viral DNA. The structural formula for these compounds is shown below as 1. ##STR2##
In the Reist compounds, B is a purine or pyrimidine base: R.sub.1 and R.sub.2 together complete a .beta.-pentofuranose sugar or R.sub.1 is H and R.sub.2 is H or hydroxymethyl; R.sub.3 is H or OH: X is H, OH or together with Y is carbonyl oxygen and Y can also be H; Z.sub.1 and Z.sub.2 are H or alkyl. These art compounds are generally distinguished from the compounds of the instant invention by 1) the ether-oxygen link to the carbon atom attached to the base which is intended to preserve or mimic the acetal oxygen bond of a pentofuranose sugar ring; and 2) the phosphate modification is a phosphonoalkylene moiety. In contrast, the acyclic sugar analog component of the instant compounds is comprised of an all carbon atom backbone up to a phosphonomethoxy moiety.
Similarly, synthesis and anti-Herpes-Virus activity of phosphate and phosphonate derivatives of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (Formula 2) was disclosed by Prisbe, et al., in J. Med. Chem., 1986, 29, 671. ##STR3##
More closely related are adenine phosphonic acid analogs (Formula 3) and their syntheses which were disclosed in the UK Patent Application of Holy, et al., GB 2, 134, 907A published Aug. 22, 1984. ##STR4##
In formula 3, R.sub.2 and R.sub.3 are H or together complete a ribonucleoside ring; and both R.sub.4 are alternately a hydrogen and --CH.sub.2 P(O)(OH).sub.2 group.
A preferred example of one of these compounds, known as (S)-HPMPA (Formula 4) was disclosed by DeClercq, et al., in Nature, 1986, 323, pp. 464-467 and earlier by Holy, et al., Nucleic Acids Research, Symposium Series No. 14, 1984 pp. 277-278.In our hands,(S)-HPMPA is only slightly active in mice inoculated with Herpes simplex virus- 2. In a 21 day protocol 30% of a group of animals treated i.p. with 50 mg/kg/day of(S)-HPMPA survived. ##STR5##
There is no teaching contained in these references, or a suggested combination thereof, which would make obvious the compounds, compositions, and use involved in the present invention.